PROJECT SUMMARY/ABSTRACT Inhibition remarkably clinical with most priming therapy, of epidermal growth factor receptor (EGFR) prior to the delivery of photodynamic therapy (PDT) can improve treatment efficacy in animal models of non-small cell lung cancer (NSCLC). Currently, use of EGFR tyrosine kinase inhibitors (TKIs) for treatment of patients with NSCLC is limited to those EGFR mutated disease. EGFR-TKI therapy is typically continued until time of disease progression since patients eventually develop EGFR-TKI resistant disease. Here, we propose to use EGFR-TKIs as a brief, therapy for several days rather than as a daily continuous therapeutic. Importantly, as a priming we hypothesize thatEGFR-TKI pretreatment will improve the therapeutic efficacy of PDT (and ionizing radiotherapy, XRT) through an innate immune response-dependent mechanism. the EGFR EGFR-TKI priming involve EGFR-TKIs damage Indeed, demonstrate TKI/PDT). lymphocytes cells) innate notwithstanding investigate clinical XRT. vascular augments and demonstrate Significantly, we posit that use of EGFR-TKIs as a priming approach to stimulate innate immunity is relevant to patients with wild-type disease. However, its potential efficacy may not be apparent in the setting of daily continuous therapy due to suppression of innate and adaptive immunity by prolonged use of EGFR-TKIs. As a therapy, EGFR-TKIs could augment responses to PDT and XRT through multiple mechanisms that cooperation between the EGFR-TKIs and PDT or XRT to promote tumor-directed innate immunity. may increase neutrophil activation in tumors receiving PDT or XRT, serving to increase vascular and/or stimulate other cells of the innate immune system, such as innate immune lymphocytes. our published data show EGFR-TKI to increase vascular damage to PDT, and preliminary data increases in tumor-localized neutrophil activation when PDT is preceded by EGFR-TKI (EGFR- Additionally, EGFR-TKIs and PDT or XRT may cooperatively increase numbers of innate immune and the immunologic visibility of target cells (e.g., tumor cells or tumor-associated endothelial to these lymphocytes. In fact, in preliminary data the efficacy of EGFR-TKI/PDT is dependent on the immune lymphocytes NK and ?? T cells. We note that the role of ?? T cells in response to EGFR-TKI, combinations with PDT or XRT, is a novel area of investigation. Moreover, we uniquely EGFR-TKI priming with proton XRT. Knowledge gained from this proposal will guide selection of a approach to EGFR-TKI priming with radiation therapy, whether it be with PDT, photon XRT, or proton Toward this goal, we will address the following aims: To define the role of neutrophils in promoting damage when PDT is preceded by EGFR-TKI. To ascertain how pretreatment with EGFR-TKI the response of innate immune l ymphocytes to PDT-treated tumors. To establish the efficacy innate immune effects of EGFR-TKIs combined with ionizing radiation therapies (photon and proton) and application in control of lung metastasis. Aim 1. Aim 2. Aim 3.